The purpose of this investigation is to elucidate the pathogenesis of hepatitis C virus (HCV) infection. This study is based on the hypothesis that viral, immunologic, genetic, and environmental factors affect hepatitis C progression. To examine the relative importance of multiple factors, in a representative setting and with appropriate power, a series of integrated experiments has been designed for specimens from a large cohort of injecting drug users (IDUs) who have been followed semiannually since 1988. The study population is 1356 IDUs, including 1203 with antibodies to HCV in 1988, 378 infected with HCV and HIV, 67 who have acquired HCV, and 86 persistently HCV-negative IDUs. By testing stored sera, persistence of HCV RNA will be assessed and, along with the results of ongoing ALT testing and clinical importance of various factors in the pathogenesis of HCV will be evaluated by comparing their occurrence among 125 cases of progressive liver disease, 86 persistently HCV-negative IDUs, and controls that are carefully matched for confounders such as duration of drug use. Viral studies will include RNA concentration, strain variation, and quasispecies distribution in sera from 1988. Lymphocyte proliferative and cytotoxic responses, cytokine levels; the distribution of HLA haplotypes and gene markers; and the prevalence of HIV, chronic hepatitis B, hepatitis G, and alcohol use will also be assessed as correlates of disease progression or apparent absence of infection. Anticipated recruitment of 40 new incident cases and the existing 67 HCV seroconverters permit unique analysis of early events and a setting for testing candidate vaccines.